title: Galactose-decorated reduction-sensitive degradable chimaeric polymersomes as a multifunctional nanocarrier to efficiently chaperone apoptotic proteins into hepatoma cells.
abstract: Hepatoma-targeting reduction-sensitive chimaeric biodegradable polymersomes were designed and developed based on galactose-poly(ethylene glycol)-poly(ε-caprolactone) (Gal-PEG-PCL), PEG-PCL-poly(2-(diethylamino)ethyl methacrylate) (PEG-PCL-PDEA, asymmetric), and PEG-SS-PCL for facile loading and triggered intracellular delivery of proteins. The chimaeric polymersomes formed from PEG-PCL-PDEA and PEG-SS-PCL had a monodisperse distribution with average sizes ranging from 95.5 to 199.2 nm depending on PEG-SS-PCL contents. Notably, these polymersomes displayed decent loading of bovine serum albumin (BSA), ovalbumin (OVA), and cytochrome C (CC) proteins likely due to presence of electrostatic and hydrogen bonding interactions between proteins and PDEA block located in the interior of polymersomes. The in vitro release studies showed that protein release was largely accelerated under a reductive condition containing 10 mM dithiothreitol (DTT). For example, ca. 77.2 and 22.1% of FITC-BSA were released from CP(SS50) (chimaeric polymersomes containing 50 wt % PEG-SS-PCL) at 37 °C in 12 h in the presence and absence of 10 mM DTT, respectively. Confocal microscopy showed that FITC-CC-loaded Gal-decorated CP(SS40) could efficiently deliver and release FITC-CC into HepG2 cells following 24 h treatment, in contrast to little or negligible fluorescence detected in HepG2 cells treated with FITC-CC-loaded nontargeting polymersomes or free CC. MTT assays revealed that CC-loaded Gal-decorated CP(SS40) exhibited apparent targetability and pronounced antitumor activity to HepG2 cells, in which cell viabilities decreased from 81.9, 60.6, 49.5, 42.2 to 31.5% with increasing Gal-PEG-PCL contents from 0, 10, 20, 30 to 40 wt %. Most remarkably, granzyme B-loaded Gal-decorated chimaeric polymersomes effectively caused apoptosis of HepG2 cells with a markedly low half-maximal inhibitory concentration (IC(50)) of 2.7 nM. These reduction-responsive chimaeric biodegradable polymersomes offer a multifunctional platform for efficient intracellular protein delivery.
authors.affiliation: Biomedical Polymers Laboratory, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Huanli
authors.initials: H
authors.lastname: Sun
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D037263:Asialoglycoprotein Receptor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005690:Galactose / Q000737:chemistry*; D053804:Granzymes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D053769:Nanocapsules / Q000737:chemistry*; D010047:Ovalbumin / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D037263:Asialoglycoprotein Receptor; D053769:Nanocapsules; D011091:Polyesters; C016240:polycaprolactone; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D010047:Ovalbumin; D045304:Cytochromes c; D053804:Granzymes; D005690:Galactose